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Molecular and Cellular Biology, October 1999, p. 6500-6508, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Mouse Receptor Interacting Protein 3 Does Not Contain a Caspase-Recruiting or a Death Domain but Induces Apoptosis and Activates NF-kappa B

Nanette J. Pazdernik,1,2 David B. Donner,2,3 Mark G. Goebl,1,3 and Maureen A. Harrington1,3,*

Departments of Biochemistry and Molecular Biology1 and Microbiology and Immunology,2 Indiana University School of Medicine, and Walther Cancer Institute,3 Indianapolis, Indiana 46202

Received 26 May 1999/Accepted 29 June 1999

The death domain-containing receptor superfamily and their respective downstream mediators control whether or not cells initiate apoptosis or activate NF-kappa B, events critical for proper immune system function. A screen for upstream activators of NF-kappa B identified a novel serine-threonine kinase capable of activating NF-kappa B and inducing apoptosis. Based upon domain organization and sequence similarity, this novel kinase, named mRIP3 (mouse receptor interacting protein 3), appears to be a new RIP family member. RIP, RIP2, and mRIP3 contain an N-terminal kinase domain that share 30 to 40% homology. In contrast to the C-terminal death domain found in RIP or the C-terminal caspase-recruiting domain found in RIP2, the C-terminal tail of mRIP3 contains neither motif and is unique. Despite this feature, overexpression of the mRIP3 C terminus is sufficient to induce apoptosis, suggesting that mRIP3 uses a novel mechanism to induce death. mRIP3 also induced NF-kappa B activity which was inhibited by overexpression of either dominant-negative NIK or dominant-negative TRAF2. In vitro kinase assays demonstrate that mRIP3 is catalytically active and has autophosphorylation site(s) in the C-terminal domain, but the mRIP3 catalytic activity is not required for mRIP3 induced apoptosis and NF-kappa B activation. Unlike RIP and RIP2, mRIP3 mRNA is expressed in a subset of adult tissues and is thus likely to be a tissue-specific regulator of apoptosis and NF-kappa B activity. While the lack of a dominant-negative mutant precludes linking mRIP3 to a known upstream regulator, characterizing the expression pattern and the in vitro functions of mRIP3 provides insight into the mechanism(s) by which cells modulate the balance between survival and death in a cell-type-specific manner.

* Corresponding author. Mailing address: 1044 West Walnut St., R4-359, Indianapolis, IN 46202. Phone: (317) 274-7527. Fax: (317) 274-7592. E-mail: mharrin{at}iupui.edu.

Molecular and Cellular Biology, October 1999, p. 6500-6508, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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